LL-37 is a multifunctional 37-residue antimicrobial peptide produced by human epithelial cells and immune cells by proteolytic cleavage from the C-terminal portion of the hCAP-18 protein. The 18-kDa hCAP18 is synthesized and stored in granules and lamellar bodies. Following stimulation by proinflammatory signals, hCAP18 is released into the extracellular environment and cleaved by proteinase 3 in neutrophils and kallikrein in keratinocytes and the N-terminal 37 amino acid form the alpha-helical LL-37 peptide that then forms higher order oligomers in solution.
Unlike other antimicrobial peptides, LL-37 is protected from proteolytic degradation. Its positive charge allows it to preferentially associate with negatively charged phospholipid membranes. Furthermore, it assumes a primarily alpha-helical shape during membrane interactions, resulting in unilateral segregation of its hydrophobic residues. This allows for membrane penetration, formation of transmembrane pores, and bacterial death by leakage of bacterial cell contents.
In addition to LL-37's ability to kill bacteria, it can also regulate the activities of multiple innate immune receptors. High levels of LL-37 are associated with autoimmune diseases such as psoriasis, systemic lupus erythromatosis, and asthma, suggesting that overexpression of LL-37 could be linked to diseases.
Indeed, both pro- and anti-inflammatory functions have been assigned to LL-37 and these activities may be modulated by the microenvironment and disease.
Exposure to LL-37 results in recruitment of inflammatory cells, induction of M1 macrophages, and stimulation of inflammatory responses such as inflammasome activation and type I IFN production. For example, LL-37 influences inflammatory cell recruitment and macrophage phenotype.
However, LL-37 also has strong anti-inflammatory effects such as neutralization of TLR4 signal transduction in response to lipopolysaccharides (LPS; also known as endotoxin), down modulation of inflammatory cytokine responses, and preventing inflammatory responses to pathogenic bacteria.
It is understood that the Toll-like receptor (TLR) family plays an instructive role in innate immune responses against microbial pathogens, as well as the subsequent induction of adaptive immune responses. TLRs recognize specific molecular patterns found in a broad range of bacterial and viral pathogens, triggering inflammatory and antiviral responses, as well as dendritic cell maturation, which result in the eradication of invading pathogens. A thorough review of TLR signaling by T. Kawai et al. can be found in Cell Death and Differentiation (2006) 13, 816-825.
Dysregulation of TLR signaling has been reported to be important for the development of autoimmunity. Modulation of TLR function by LL-37 can be considered an anti-inflammatory effect. For example, LL-37 down-regulates signaling through TLR4 via binding of its ligand, LPS, as well as through interruption of TLR4 receptor complex function in dendritic cells (DCs) and macrophages. This results in lower levels of proinflammatory cytokine production when LL-37 and LPS are present simultaneously (see M Kahlenberg et al.: Little Peptide, Big Effects: the role of LL-37 in inflammation and Autoimmune Disease, J. Immunol. 2013; 191: 4895-4901)
Thus, based on the current knowledge on LL-37's role played in autoimmune diseases, and its potential to suppress inflammatory response, a balanced approach to better use LL-37 is desired. This disclosure identifies several antagonists of LL-37 and provides such advantages compared to other conventional compound selection of LL-37 antagonists.